Gene Therapy Protocols pp 133-160

Part of the Methods in Molecular Biology™ book series (MIMB, volume 434) | Cite as

PEGylated Adenovirus for Targeted Gene Therapy

  • Catherine R.
  • O’ Riordan
  • Antonius Song

Summary

Bifunctional polyethylene glycol (PEG) molecules provide a novel approach to retargeting viral vectors without the need to genetically modify the vector. Modification of the surface of adenovirus with heterofunctional PEG allows further modification of the capsid with ligands. In addition, heterofunctional PEG modification ablates the normal tropism of the virus and reduces transduction of non-target tissues in vivo. Moreover, the addition of PEG chains to the surface of the virus shields antigen-binding sites, significantly reducing the susceptibility of the virus to antibody neutralization. Finally, T cell subsets from mice exposed to the PEGylated vector demonstrate a marked decrease in Th1 and Th2 responses, suggesting that PEG modification may help reduce the immune response to the vector.

Key Words

Adenovirus PEGylation targeting FGF2 innate immunity adaptive immunity antibody neutralization 

Reference

  1. 1.
    Bergelson JM, Cunningham JA, Droguett G, Kurt-Jones EA, Krithivas A, Hong JS, Horwitz MS, Crowell RL, Finberg RW. (1997) Isolation of a common receptor for Coxsackie B viruses and Adenoviruses 2 and 5. Science 275(5304):1320–3.CrossRefPubMedGoogle Scholar
  2. 2.
    Tomko RP, Xu R, Philipson L. (1997) HCAR and MCAR: the human and mouse cellular receptors for subgroup C adenoviruses and group B coxsackieviruses. Proc Natl Acad Sci USA 94(7):3352–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Wickham TJ, Filardo EJ, Cheresh DA, Nemerow GR. (1994) Integrin alpha v beta 5 selectively promotes adenovirus mediated cell membrane permeabilization. J Cell Biol 127(1):257–64.CrossRefPubMedGoogle Scholar
  4. 4.
    Wickham TJ, Mathias P, Cheresh DA, Nemerow GR. (1993) Integrins alpha v beta 3 and alpha v beta 5 promote adenovirus internalization but not virus attachment. Cell 73(2):309–19.CrossRefPubMedGoogle Scholar
  5. 5.
    Nakamura T, Sato K, Hamada H. (2003) Reduction of natural adenovirus tropism to the liver by both ablation of fiber-coxsackievirus and adenovirus receptor interaction and use of replaceable short fiber. J Virol 77(4):2512–21.CrossRefPubMedGoogle Scholar
  6. 6.
    Smith TA, Idamakanti N, Rollence ml, Marshall-Neff J, Kim J, Mulgrew K, Nemerow GR, Kaleko M, Stevenson SC. (2003) Adenovirus serotype 5 fiber shaft influences in vivo gene transfer in mice. Hum Gene Ther 14(8):777–87.CrossRefPubMedGoogle Scholar
  7. 7.
    Smith TA, Idamakanti N, Marshall-Neff J, Rollence ml, Wright P, Kaloss M, King L, Mech C, Dinges L, Iverson WO, Sherer AD, Markovits JE, Lyons RM, Kaleko M, Stevenson SC. (2003) Receptor interactions involved in adenoviral-mediated gene delivery after systemic administration in non-human primates Hum Gene Ther 14(17):1595–604.CrossRefPubMedGoogle Scholar
  8. 8.
    Vigne E, Dedieu JF, Brie A, Gillardeaux A, Briot D, Benihoud K, Latta-Mahieu M, Saulnier P, Perricaudet M, Yeh P. (2003) Genetic manipulations of adenovirus type 5 fiber resulting in liver tropism attenuation. Gene Ther 10(2):153–62.CrossRefPubMedGoogle Scholar
  9. 9.
    Bruder JT, Kovesdi I. (1997) Adenovirus infection stimulates the Raf/MAPK signaling pathway and induces interleukin-8 expression. J Virol 71(1):398–404.PubMedGoogle Scholar
  10. 10.
    Lieber A, He CY, Meuse L, Schowalter D, Kirillova I, Winther B, Kay MA. (1997) The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol 71(11):8798–807.PubMedGoogle Scholar
  11. 11.
    Muruve DA, Barnes MJ, Stillman IE, Libermann TA. (1999) Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther 10(6):965–76.CrossRefPubMedGoogle Scholar
  12. 12.
    Shifrin AL, Chirmule N, Gao GP, Wilson JM, Raper SE. (2005) Innate immune responses to adenoviral vector-mediated acute pancreatitis. Pancreas 30(2):122–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Elkon KB, Liu CC, Gall JG, Trevejo J, Marino MW, Abrahamsen KA, Song X, Zhou JL, Old LJ, Crystal RG, Falck-Pedersen E. (1997) Tumor necrosis factor alpha plays a central role in immune-mediated clearance of adenoviral vectors. Proc Natl Acad Sci USA 94(18):9814–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Zaiss AK, Liu Q, Bowen GP, Wong NC, Bartlett JS, Muruve DA. (2002) Differential activation of innate immune responses by adenovirus and adeno-associated virus vectors. J Virol 76(9):4580–90.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu Q, Muruve DA. (2003) Molecular basis of the inflammatory response to adenovirus vectors. Gene Ther 10(11):935–40.CrossRefPubMedGoogle Scholar
  16. 16.
    Jooss K, Ertl HC, Wilson JM. (1998) Cytotoxic T-lymphocyte target proteins and their major histocompatibility complex class I restriction in response to adenovirus vectors delivered to mouse liver. J Virol. 72(4):2945–54.PubMedGoogle Scholar
  17. 17.
    Yang Y, Jooss KU, Su Q, Ertl HC, Wilson JM. (1996) Immune responses to viral antigens versus transgene product in the elimination of recombinant adenovirus-infected hepatocytes in vivo. Gene Ther. 3(2):137–44.PubMedGoogle Scholar
  18. 18.
    Yang Y, Wilson JM. (1995) Clearance of adenovirus-infected hepatocytes by MHC class I-restricted CD4+ CTLs in vivo. J Immunol. 155(5):2564–70.PubMedGoogle Scholar
  19. 19.
    Leissner P, Legrand V, Schlesinger Y, Hadji DA, van Raaij M, Cusack S, Pavirani A, Mehtali M. (2001) Influence of adenoviral fiber mutations on viral encapsidation, infectivity and in vivo tropism. Gene Ther. 8(1):49–57.CrossRefPubMedGoogle Scholar
  20. 20.
    Alemany R, Curiel DT. (2001) CAR-binding ablation does not change biodistribution and toxicity of adenoviral vectors. Gene Ther. 8(17):1347–53.CrossRefPubMedGoogle Scholar
  21. 21.
    Einfeld DA, Schroeder R, Roelvink PW, Lizonova A, King CR, Kovesdi I, Wickham TJ. (2001) Reducing the native tropism of adenovirus vectors requires removal of both CAR and integrin interactions. J Virol. 75(23):11284–91.CrossRefPubMedGoogle Scholar
  22. 22.
    Mizuguchi H, Koizumi N, Hosono T, Ishii-Watabe A, Uchida E, Utoguchi N, Watanabe Y, Hayakawa T. (2002) CAR- or alphav integrin-binding ablated adenovirus vectors, but not fiber-modified vectors containing RGD peptide, do not change the systemic gene transfer properties in mice. Gene Ther. 9(12):769–76.CrossRefPubMedGoogle Scholar
  23. 23.
    Smith T, Idamakanti N, Kylefjord H, Rollence M, King L, Kaloss M, Kaleko M, Stevenson SC. (2002) In vivo hepatic adenoviral gene delivery occurs independently of the coxsackievirus-adenovirus receptor. Mol Ther. 5(6):770–9.CrossRefPubMedGoogle Scholar
  24. 24.
    Koizumi N, Kawabata K, Sakurai F, Watanabe Y, Hayakawa T, Mizuguchi H. (2006) Modified adenoviral vectors ablated for coxsackievirus-adenovirus receptor, alpha\(_{\rm v}\) integrin, and heparan sulfate binding reduce in vivo tissue transduction and toxicity. Hum Gene Ther. 17(3):264–79.CrossRefPubMedGoogle Scholar
  25. 25.
    Wickham TJ, Segal DM, Roelvink PW, Carrion ME, Lizonova A, Lee GM, Kovesdi I. (1996) Targeted adenovirus gene transfer to endothelial and smooth muscle cells by using bispecific antibodies. J Virol. 70(10):6831–8.PubMedGoogle Scholar
  26. 26.
    Douglas JT, Rogers BE, Rosenfeld ME, Michael SI, Feng M, Curiel DT. (1996) Targeted gene delivery by tropism-modified adenoviral vectors. Nat Biotechnol. 14(11):1574–8CrossRefPubMedGoogle Scholar
  27. 27.
    Wickham TJ, Lee GM, Titus JA, Sconocchia G, Bakacs T, Kovesdi I, Segal DM. (1997) Targeted adenovirus-mediated gene delivery to T cells via CD3. J Virol. 71(10):7663–9.PubMedGoogle Scholar
  28. 28.
    Goldman CK, Rogers BE, Douglas JT, Sosnowski BA, Ying W, Siegal GP, Baird A, Campain JA, Curiel DT. (1997) Targeted gene delivery to Kaposi’s sarcoma cells via the fibroblast growth factor receptor. Cancer Res. 57(8):1447–51.PubMedGoogle Scholar
  29. 29.
    Rogers BE, Douglas JT, Ahlem C, Buchsbaum DJ, Frincke J, Curiel DT. (1997) Use of a novel cross-linking method to modify adenovirus tropism. Gene Ther. 4(12):1387–92.CrossRefPubMedGoogle Scholar
  30. 30.
    Rancourt C, Rogers BE, Sosnowski BA, Wang M, Piche A, Pierce GF, Alvarez RD, Siegal GP, Douglas JT, Curiel DT. (1998) Basic fibroblast growth factor enhancement of adenovirus-mediated delivery of the herpes simplex virus thymidine kinase gene results in augmented therapeutic benefit in a murine model of ovarian cancer. Clin Cancer Res. 4(10):2455–61.PubMedGoogle Scholar
  31. 31.
    Gu DL, Gonzalez AM, Printz MA, Doukas J, Ying W, D’Andrea M, Hoganson DK, Curiel DT, Douglas JT, Sosnowski BA, Baird A, Aukerman SL, Pierce GF. (1999) Fibroblast growth factor 2 retargeted adenovirus has redirected cellular tropism: evidence for reduced toxicity and enhanced antitumor activity in mice. Cancer Res. 59(11):2608–14.PubMedGoogle Scholar
  32. 32.
    Blackwell JL, Miller CR, Douglas JT, Li H, Reynolds PN, Carroll WR, Peters GE, Strong TV, Curiel DT. (1999) Retargeting to EGFR enhances adenovirus infection efficiency of squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 125(8):856–63.PubMedGoogle Scholar
  33. 33.
    Doukas J, Hoganson DK, Ong M, Ying W, Lacey DL, Baird A, Pierce GF, Sosnowski BA. (1999) Retargeted delivery of adenoviral vectors through fibroblast growth factor receptors involves unique cellular pathways. FASEB J. 13(11):1459–66.PubMedGoogle Scholar
  34. 34.
    Yoon SK, Mohr L, O’Riordan CR, Lachapelle A, Armentano D, Wands JR. (2000) Targeting a recombinant adenovirus vector to HCC cells using a bifunctional Fab-antibody conjugate. Biochem Biophys Res Commun. 272(2):497–504.CrossRefPubMedGoogle Scholar
  35. 35.
    Trepel M, Grifman M, Weitzman MD, Pasqualini R. (2000) Molecular adaptors for vascular-targeted adenoviral gene delivery. Hum Gene Ther. 11(14):1971–81.CrossRefPubMedGoogle Scholar
  36. 36.
    Tillman BW, Hayes TL, DeGruijl TD, Douglas JT, Curiel DT. (2000) Adenoviral vectors targeted to CD40 enhance the efficacy of dendritic cell-based vaccination against human papillomavirus 16-induced tumor cells in a murine model. Cancer Res. 60(19):5456–63.PubMedGoogle Scholar
  37. 37.
    Reynolds PN, Zinn KR, Gavrilyuk VD, Balyasnikova IV, Rogers BE, Buchsbaum DJ, Wang MH, Miletich DJ, Grizzle WE, Douglas JT, Danilov SM, Curiel DT. (2000) A targetable, injectable adenoviral vector for selective gene delivery to pulmonary endothelium in vivo. Mol Ther. 2(6):562–78.CrossRefPubMedGoogle Scholar
  38. 38.
    Ebbinghaus C, Al-Jaibaji A, Operschall E, Schoffel A, Peter I, Greber UF, Hemmi S. (2001) Functional and selective targeting of adenovirus to high-affinity Fc gamma receptor I-positive cells by using a bispecific hybrid adapter. J Virol. 75(1):480–9.CrossRefPubMedGoogle Scholar
  39. 39.
    Hoganson DK, Sosnowski BA, Pierce GF, Doukas J. (2001) Uptake of adenoviral vectors via fibroblast growth factor receptors involves intracellular pathways that differ from the targeting ligand. Mol Ther. 3(1):105–12.CrossRefPubMedGoogle Scholar
  40. 40.
    Grill J, Van Beusechem VW, Van Der Valk P, Dirven CM, Leonhart A, Pherai DS, Haisma HJ, Pinedo HM, Curiel DT, Gerritsen WR. (2001) Combined targeting of adenoviruses to integrins and epidermal growth factor receptors increases gene transfer into primary glioma cells and spheroids. Clin Cancer Res. 7(3):641–50.PubMedGoogle Scholar
  41. 41.
    Nettelbeck DM, Miller DW, Jerome V, Zuzarte M, Watkins SJ, Hawkins RE, Muller R, Kontermann RE. (2001) Targeting of adenovirus to endothelial cells by a bispecific single-chain diabody directed against the adenovirus fiber knob domain and human endoglin (CD105). Mol Ther. 3(6):882–91.CrossRefPubMedGoogle Scholar
  42. 42.
    Israel BF, Pickles RJ, Segal DM, Gerard RD, Kenney SC. (2001) Enhancement of adenovirus vector entry into CD70-positive B-cell lines by using a bispecific CD70-adenovirus fiber antibody. J Virol. 75(11):5215–21.CrossRefPubMedGoogle Scholar
  43. 43.
    Smith JS, Keller JR, Lohrey NC, McCauslin CS, Ortiz M, Cowan K, Spence SE. (1999) Redirected infection of directly biotinylated recombinant adenovirus vectors through cell surface receptors and antigens. Proc Natl Acad Sci U S A. 96(16):8855–60CrossRefPubMedGoogle Scholar
  44. 44.
    Romanczuk H, Galer CE, Zabner J, Barsomian G, Wadsworth SC, O’Riordan CR. (1999) Modification of an adenoviral vector with biologically selected peptides: a novel strategy for gene delivery to cells of choice. Hum Gene Ther. 10(16):2615–26.CrossRefPubMedGoogle Scholar
  45. 45.
    Romanczuk H, Galer CE, Zabner J, Barsomian G, Wadsworth SC, O’Riordan CR. (1999) Dressing up adenoviruses to modify their tropism. Hum Gene Ther. 10(16):2575–6.CrossRefPubMedGoogle Scholar
  46. 46.
    Drapkin PT, O’Riordan CR, Yi SM, Chiorini JA, Cardella J, Zabner J, Welsh MJ. (2000) Targeting the urokinase plasminogen activator receptor enhances gene transfer to human airway epithelia. J Clin Invest. 105(5):589–96.CrossRefPubMedGoogle Scholar
  47. 47.
    Lanciotti J, Song A, Doukas J, Sosnowski B, Pierce G, Gregory R, Wadsworth S, O’Riordan C. (2003) Targeting adenoviral vectors using heterofunctional polyethylene glycol FGF2 conjugates. Mol Ther. 8(1):99–107CrossRefPubMedGoogle Scholar
  48. 48.
    Fisher KD, Stallwood Y, Green NK, Ulbrich K, Mautner V, Seymour LW. (2001) Polymer-coated adenovirus permits efficient retargeting and evades neutralizing antibodies. Gene Ther. 8(5):341–8CrossRefPubMedGoogle Scholar
  49. 49.
    O’Riordan CR, Lachapelle A, Delgado C, Parkes V, Wadsworth SC, Smith AE, Francis GE. (1999) PEGylation of adenovirus with retention of infectivity and protection from neutralizing antibody in vitro and in vivo. Hum Gene Ther. 10(8):1349–58.CrossRefPubMedGoogle Scholar
  50. 50.
    Croyle MA, Chirmule N, Zhang Y, Wilson JM. (2001) “Stealth’ adenoviruses blunt cell-mediated and humoral immune responses against the virus and allow for significant gene expression upon readministration in the lung. J Virol. 75(10):4792–801.CrossRefPubMedGoogle Scholar
  51. 51.
    Croyle MA, Chirmule N, Zhang Y, Wilson JM. (2002) PEGylation of E1-deleted adenovirus vectors allows significant gene expression on readministration to liver. Hum Gene Ther. 13(15):1887–900.CrossRefPubMedGoogle Scholar
  52. 52.
    Croyle MA, Le HT, Linse KD, Cerullo V, Toietta G, Beaudet A, Pastore L. (2005) PEGylated helper-dependent adenoviral vectors: highly efficient vectors with an enhanced safety profile. Gene Ther. 12(7):579–87.CrossRefPubMedGoogle Scholar
  53. 53.
    Richter AW, Akerblom E. (1983) Antibodies against polyethylene glycol produced in animals by immunization with monomethoxy polyethylene glycol modified proteins. Int Arch Allergy Appl Immunol. 70(2):124–31.CrossRefPubMedGoogle Scholar
  54. 54.
    Delgado C, Patel JN, Francis GE, Fisher D. (1990) Coupling of poly(ethylene glycol) to albumin under very mild conditions by activation with tresyl chloride: characterization of the conjugate by partitioning in aqueous two-phase systems. Biotechnol Appl Biochem. 12(2):119–28.PubMedGoogle Scholar
  55. 55.
    Francis GE, Fisher D, Delgado C, Malik F, Gardiner A, Neale D. (1998) PEGylation of cytokines and other therapeutic proteins and peptides: the importance of biological optimization of coupling techniques. Int J Hematol. 68(1):1–18.CrossRefPubMedGoogle Scholar
  56. 56.
    Armentano D, Zabner J, Sacks C, Sookdeo CC, Smith MP, St George JA, Wadsworth SC, Smith AE, Gregory RJ. (1997) Effect of the E4 region on the persistence of transgene expression from adenovirus vectors. J Virol. 71(3):2408–16.PubMedGoogle Scholar
  57. 57.
    Yu D, Wolf JK, Scanlon M, Price JE, Hung MC. (1993) Enhanced c-erbB-2/neu expression in human ovarian cancer cells correlates with more severe malignancy that can be suppressed by E1A. Cancer Res. 53(4):891–8.PubMedGoogle Scholar
  58. 58.
    Maizel JV Jr, White DO, Scharff MD. (1968) The polypeptides of adenovirus. I. Evidence for multiple protein components in the virion and a comparison of types 2, 7A, and 12. Virology. 36(1):115–25.CrossRefPubMedGoogle Scholar
  59. 59.
    Green, M., Pina, M., Kimes, R., Wensik, P., Machattie, L., and Thomas Jr., C. (1967) Adenovirus DNA. Molecular weight and conformation. Proc.Natl. Acad. Sci. USA 57, 1302–1309Google Scholar
  60. 60.
    van der Eb AJ, van Kesteren LW, van Bruggen EF. (1969) Structural properties of adenovirus DNA’s. Biochim Biophys Acta. 182(2):530–41PubMedGoogle Scholar
  61. 61.
    Lappi DA, Matsunami R, Martineau D, Baird A. (1993) Reducing the heterogeneity of chemically conjugated targeted toxins: homogeneous basic FGF-saporin. Anal. Biochem. 212(2):446–51.CrossRefPubMedGoogle Scholar
  62. 62.
    Zhang JD, Cousens LS, Barr PJ, Sprang SR. (1991) Three-dimensional structure of human basic fibroblast growth factor, a structural homolog of interleukin 1 beta. Proc Natl Acad Sci U S A. 88(8):3446–50.CrossRefPubMedGoogle Scholar
  63. 63.
    Heid CA, Stevens J, Livak KJ, Williams PM. (1996) Real time quantitative PCR. Genome Res. 6(10):986–94.CrossRefPubMedGoogle Scholar
  64. 64.
    Yang Y, Li Q, Ertl HC, Wilson JM. (1995) Cellular and humoral immune responses to viral antigens create barriers to lung-directed gene therapy with recombinant adenoviruses. J Virol. 69(4):2004–15PubMedGoogle Scholar
  65. 65.
    Prage L, Pettersson U, Hoglund S, Lonberg-Holm K, Philipson L. (1970) Structural proteins of adenoviruses. IV. Sequential degradation of the adenovirus type 2 virion. Virology. 42(2):341–58CrossRefPubMedGoogle Scholar
  66. 66.
    Huyghe BG, Liu X, Sutjipto S, Sugarman BJ, Horn MT, Shepard HM, Scandella CJ, Shabram P. (1995) Purification of a type 5 recombinant adenovirus encoding human p53 by column chromatography. Hum Gene Ther. 6(11):1403–16.CrossRefPubMedGoogle Scholar
  67. 67.
    O’Riordan CR, Lachapelle AL, Vincent KA, Wadsworth SC. (2000) Scaleable chromatographic purification process for recombinant adeno-associated virus (rAAV). J Gene Med. 2(6):444–54.CrossRefPubMedGoogle Scholar

Copyright information

© Humana Press, a part of Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Catherine R.
    • 1
  • O’ Riordan
    • 1
  • Antonius Song
    • 1
  1. 1.Genzyme CorporationMA

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